The aims of the proposal are in accord with the mission of the Addiction Treatment Discovery Program (ATDP): To discover potential pharmacological treatments for substance abuse in humans, with an emphasis on relapse prevention, through preclinical testing and evaluation of compounds. The principal goal of the project is to provide potential treatment agents for polydrug dependence by targeting single chemical entities that mimic the profile produced by a buprenorphine/naltrexone combination. There is evidence from both clinical and preclinical research that this combination can help prevent relapse to drug taking behaviour, including both opioids and cocaine. The target compounds lack of, or very limited, mu opioid receptor efficacy will render the compounds safe and ethically acceptable for use in both opioid using and non-opioid using addicts. Efficacy as treatment agents will also come from the compounds kappa opioid receptor antagonist activity, coupled with agonism at NOP (nociceptin) receptors and antagonism at delta opioid receptors. Lead compounds have been identified during the current funding period from within the orvinol and naltrexone series. These series have already produced several compounds of clinical or veterinary utility, including buprenorphine and naltrexone. Key, recent medicinal chemistry discoveries by our group including, 1) the role of a methyl group at C7 in the orvinol series in reducing efficacy at kappa receptors and increasing NOP activity and 2) the role of the C14 side chain in the naltrexone series in allowing substantial NOP activity to be introduced to this series of opioid antagonists, has allowed compounds with the desired profile to be developed. These discoveries will be extended; in particular, ligands from the orvinol series have been identified for further evaluation with one currently undergoing extensive in vivo testing and evaluation of its ADME-tox profile. Follow-on/back-up compounds are also being developed. The significance of this work is that it will tell us whether single compounds can be developed that can block relapse to both opioid and cocaine use, what types of relapse are blocked (drug-, stress- or cue-primed) and will allow us to move our identified candidate therapeutics closer to the clinic.